Evaluating Maternal Exposure to an Environmental Per and Polyfluoroalkyl Substances (Pfas) Mixture During Pregnancy: Adverse Maternal and Fetoplacental Effects in a New Zealand White (Nzw) Rabbit Model

Background: Per- and polyfluoroalkyl substances (PFAS) are often found in drinking water, and serum PFAS are detected in up to 99% of the population. However, very little is known about how exposure to PFAS mixtures affects maternal and fetal health.  Objective: We investigated maternal, fetal, and placental outcomes after preconceptional and gestational exposure to an environmentally relevant PFAS mixture in a New Zealand White (NZW) rabbit model.  Methods : Dams were exposed via drinking water to control (no detectable PFAS) or a PFAS mixture drinking for 32 days. The mixture was formulated with PFAS to resemble levels measured in tap water from Pittsboro, NC (10 PFAS compounds; total PFAS load = 758.6 ng/L). Dams were bred on day 7 and sacrificed on gestational day 25. Maternal, fetal, and placental outcomes were evaluated at necropsy. Thyroid hormones were measured in maternal serum and kit blood. Placental gene expression was evaluated by RNAseq and qPCR.  Results: PFAS exposure resulted in higher body weight (p=0.01), liver (p=0.01) and kidney (p=0.01) weights, blood pressure (p=0.05), and BUN:CRE ratio (p=0.04) in dams, along with microscopic changes in renal cortices. Fetal weight, measures, and histopathology were unchanged, but a significant interaction between dose and sex was detected in the fetal: placental weight ratio (p=0.036). Placental macroscopic changes were present in PFAS-exposed dams. Dam serum showed lower T4 and a higher T3:T4 ratio, although not statistically significant. RNAseq revealed that 11 of the 14 differentially expressed genes (adj. p< 0.1) are involved in placentation or pregnancy complications.  Conclusions: We report adverse maternal and placental effects of an environmentally-relevant PFAS mixture in vivo . Exposure elicited weight gain and signs of hypertension, renal injury, and a sex-specific changes in placental response. Our results indicate PFAS exposure can shift biologically relevant expression of genes involved in placentation and preeclampsia.